Quetiapine, also known as 11-[4-[2-(2-Hydroxyethoxy)ethyl]-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine and represented by the following structural formula:

Quetiapine is a psychoactive organic compound that acts as an antagonist for multiple neurotransmitter receptors in the brain and acts as an antipsychotic agent reportedly useful for treating, among other things, schizophrenia. This drug was approved under the trademark Seroquel®, by the U.S. Food and Drug Administration and it is available in the form of its hemifumarate salt. Quetiapine hemifumarate is a psychotropic agent belonging to the chemical class of dibenzothiazepine derivatives and its first synthesis was disclosed in U.S. Pat. No. 4,879,288.
U.S. Pat. No. 4,879,288 (herein after referred to as the '288 patent) discloses a process for the preparation of quetiapine or pharmaceutically acceptable salts thereof which includes hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, and hemifumarate salt.
While the '288 patent mentions that the compound of formula II (quetiapine) can form a salt with physiologically acceptable organic and inorganic acids like hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, and hemifumarate salt, only the hydrochloride, maleate and hemifumarate salts of quetiapine have been prepared.
Various processes have been reported for the preparation of quetiapine or pharmaceutically acceptable salts thereof in European patent EP 282236; PCT Publication Nos. WO 05/012274; 05/028457; 05/028458; and 05/028459.
U.S. Pat. No. 6,372,734 provides a process for the purification of crystalline quetiapine or pharmaceutically acceptable salts thereof which includes hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, in particular the hemifumarate salt, which involves crystallizing quetiapine freebase.
U.S. Patent Application No. 2006/0063927 A1 (herein after referred to as the '927 application) teaches a general preparation of pharmaceutically acceptable salts of quetiapine which comprises treating quetiapine free base with at least a stoichiometric amount of an appropriate acid, wherein the appropriate acid includes, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. While the '927 application mentions a general preparation of several acid addition salts of quetiapine; only the hemifumarate salt of quetiapine has been prepared.
PCT Publication No. WO 2006/056772 A2 discloses organic acid addition salts of quetiapine selected from the group consisting of oxalate, succinate, benzoate and formate, specifically in crystalline forms along with their XRD patterns and melting points.
U.S. Patent Application No. 2007/0072840 A1 discloses polymorphic forms of quetiapine hydrochloride designated as Forms A, B, C & amorphous, and processes for their preparation. The '840 application further discloses oxalate and maleate salts of quetiapine, specifically in crystalline forms, and processes for their preparation.
PCT Publication No. WO 2007/048870 A1 teaches a process for preparing and purifying crystalline quetiapine hemifumarate which comprises dissolving quetiapine base in a solvent, converting quetiapine base to the first quetiapine salt, cooling the mixture to precipitate the first quetiapine salt, isolating the first quetiapine salt, and converting the first quetiapine salt to quetiapine hemifumarate salt; wherein the salts which is used as first crystallization salts are e.g. tosylate or hydrohalic acid salts, preferably hydrochloride.
PCT Publication No. WO 2007/102074 A2 discloses acid addition salts of quetiapine selected from the group consisting of malate (designated as Form I characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 7.1, 9.0, 16.0, 21.0 degrees), succinate (designated as Form II characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 7.4, 9.3, 20.0, 22.5 degrees), tosylate (designated as Form III characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 11.3, 12.2, 12.7, 13.3, 17.3 degrees), tartrate (designated as Form IV characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 6.7, 9.4, 19.6, 20.6, 22.3 degrees), benzoate (designated as Form V characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 6.2, 14.1, 14.8, 19.9, 21.1, 22.1, 23.0 degrees), oxalate (designated as, Form VI characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 7.3, 10.7, 11.8, 22.4 degrees; Form VII characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 9.6, 12.6, 14.5, 16.8, 24.1 degrees), and hydrobromide (designated as Form VIII characterized by a powder X-ray diffraction pattern having peaks expressed as 2-theta at about 5.6, 16.6, 23.8, 24.8 and 26.4).
PCT Publication No. WO 2008/003270A1 discloses a method for the preparation of salts of quetiapine from the quetiapine base and the respective acid, specifically fumaric acid and oxalic acid, characterized in that the reaction is carried out in a mixture of solvents, the mixture being either a mixture of an aromatic hydrocarbon and a ketone or ester, or that of an aromatic hydrocarbon, water and a ketone or ester.
In the formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form in which it can be conveniently handled and processed. This is of critical, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.
Further, in the manufacture of oral pharmaceutical compositions, it is important that a reliable, reproducible and constant plasma concentration profile of the active pharmaceutical ingredient is provided following administration to a patient.
Chemical stability, solid state stability, and “shelf life” of the active pharmaceutical ingredient are important properties for a pharmaceutical active compound. The active pharmaceutical ingredient, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient, e.g. its chemical composition, density, hygroscopicity and solubility. Thus, in the manufacture of commercially viable and pharmaceutically acceptable drug compositions, it is important, wherever possible, to provide the active pharmaceutical ingredient in a stable form.
The discovery of new salts of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds value to the material that a formulation scientist can use the same for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Novel salts of quetiapine have now been discovered.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Solvent medium and mode of crystallization play very important role in obtaining a new salt or a crystalline form over the other.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Novel and stable polymorphic forms of quetiapine salts have now been discovered.